TMP269 is a potent and selective inhibitor of Histone deacetylase (HDAC) with IC50 values of 157nM, 97nM, 43nM, 23nM for HDAC 4, 5, 7, 9, respectively[1]. TMP269 upregulates the expression of the neurotrophic factor BMP2 and the BMP-Smad transcriptional signaling pathway, thereby preventing neuronal degeneration and improving neurological function[2]. TMP269 suppresses Lumpy skin disease virus (LSDV) replication by regulating the host's lysophosphatidic acid metabolism and blocking the activation of the MEK/ERK signaling pathway[3]. TMP269 has been widely used in preclinical models to improve rehabilitation after ischemic stroke[4].
In vitro, TMP269 treatment for 72 hours significantly induced cell death in THP-1 cells, with an IC50 value of 13μM, accompanied by activation of Caspase 3/7[5]. Treatment with 12.5μM TMP269 for 48 hours inhibited the growth of MOLM-13 cells, downregulated the expression of ribosomal proteins, and promoted cell apoptosis[6]. Incubation with 50μM TMP269 for 48 hours increased the expression of FOXO3a and induced G1/S phase arrest in AsPC-1 cells[7].
In vivo, TMP269 treatment via intraperitoneal injection at a dose of 23mg/kg/day for 10 days improved the depressive-like behaviors, alleviated the stress-induced changes in hippocampal synaptic plasticity, and increased the expression of hippocampal synaptic proteins in learned helplessness mice[8]. Intraperitoneal injection of TMP269 (50mg/kg/day) for 2 days improved the renal function of the kidney injury mouse model and alleviated the pathological changes in the kidneys[9].
References:[1] Lobera M, Madauss K P, Pohlhaus D T, et al. Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group[J]. Nature chemical biology, 2013, 9(5): 319-325.
[2] O'Mahony A G, Mazzocchi M, Morris A, et al. The class-IIa HDAC inhibitor TMP269 promotes BMP-Smad signalling and is neuroprotective in in vitro and in vivo 6-hydroxydopamine models of Parkinson's disease[J]. Neuropharmacology, 2025, 268: 110319.
[3] Cheng P, Wang X, Wang S, et al. Class IIa histone deacetylase (HDAC) inhibitor TMP269 suppresses lumpy skin disease virus replication by regulating host lysophosphatidic acid metabolism[J]. Journal of Virology, 2025, 99(2): e01827-24.
[4] Jiang Q, Ding Y, Li F, et al. Inhibition of class IIa HDACs reduces neuroinflammation via NEU1-LAMP1 regulation and promotes M2 macrophage polarization in ischemic stroke[J]. Brain Research, 2025, 1864: 149806.
[5] Asfaha Y, Bollmann L M, Skerhut A J, et al. 5-(Trifluoromethyl)-1, 2, 4-oxadiazole (TFMO)-based highly selective class IIa HDAC inhibitors exhibit synergistic anticancer activity in combination with bortezomib[J]. European Journal of Medicinal Chemistry, 2024, 263: 115907.
[6] Urwanisch L, Unger M S, Sieberer H, et al. The class IIA histone deacetylase (HDAC) inhibitor TMP269 downregulates ribosomal proteins and has anti-proliferative and pro-apoptotic effects on AML cells[J]. Cancers, 2023, 15(4): 1039.
[7] Usami M, Kikuchi S, Takada K, et al. FOXO3a activation by HDAC class IIa inhibition induces cell cycle arrest in pancreatic cancer cells[J]. Pancreas, 2020, 49(1): 135-142.
[8] Meng Y, Xiao L, Liu R, et al. Antidepressant effect and mechanism of TMP269 on stress-induced depressive-like behavior in mice[J]. Biochemical Pharmacology, 2024, 225: 116320.
[9] Li J, Yu C, Shen F, et al. Class IIa histone deacetylase inhibition ameliorates acute kidney injury by suppressing renal tubular cell apoptosis and enhancing autophagy and proliferation[J]. Frontiers in Pharmacology, 2022, 13: 946192.